Si-Wei Chen, M.A.
Schizophrenia: Etiology, Neurobiology, and Treatments abstract
Advisor: Anisa Abi-Dargham
Ming-Hui Cheng, M.A.
Bacterial and Human AlkB Proteins Repair DNA Alkylation Damage in Human Cells abstract
Advisor: John Hunt
Yi-Shan Chou, M.A.
The Applications of Pharmacogenomics in Clinical Drug Development abstract
Advisor: Daniel Kalderon
Akiva Felt, M.A.
The Pharmacological Treatment of Tourette's Syndrome abstract
Advisor: Roy Boorady
Aileen Fitzmaurice, M.A.
RNA Interference; Very Promising, But Will it Deliver? abstract
Advisor: Daniel Kalderon
Tianhua Guo, M.A.
Biology of GIST: Molecular Mechanisms and Target Therapy abstract
Advisor: Cristina Antonescu
Asya Haney M.A.
Will Advexin Lead the US Towards a Brighter Future in Gene Therapy? abstract
Advisor: Carol Prives
Danielle Hanyian Ho, M.A.
Slow versus Fast Muscle Derived Stem Cells for Muscle Regeneration in mdx Mutant Mice abstract
Advisor: Margaret Stuber
Kathy E. Karasiewicz, M.A.
Autoimmunity and Mechanisms of Immunosuppression abstract
Advisor: Betty Diamond
Yuan-Chieh Ku, M.A.
The Prospect of DNA Sequencing Technology abstract
Advisor: Jim Russo
Jennifer J. Lee, M.A.
Prion Diseases: Fatal Diseases to Be Tackled in the Biological Research, Public Health, and Legal Arenas abstract
Advisor: Daniel Kalderon
Ling Yue Lee, M.A.
Middle Temporal Area’s Role in Visual Motion Processing: Motion Coherence abstract
Advisor: Vincent Ferrera
Gregory Loiseau, M.A.
Human Papillomavirus, Transformation and Vaccination abstract
Advisor: Lili Yamasaki
Jamie L. Maddux, M.A.
The War on Cancer with Emphasis on New Developments in p53, EGFR, and VEGF abstract
Advisor: Larry Chasin
Daniel J. Moskovic, M.A.
Interstrand Crosslinks: Characterization, Repair, and Clinical Significance abstract
Advisor: Alvin Krasna
Sanaa Musvee, M.A.
Overview of Acne Vulgaris and Current Treatment Procedures abstract
Advisor: Daniel Kalderon
Mahwish Natalia, M.A.
Cancer as a Stem Cell Disease abstract
Advisor: Daniel Kalderon
P. Peter Nguyen, M.A.
RNAi – Mode of Action and Therapeutic Implications abstract
Advisor: Ron Prywes
Rocío Kennia Pérez, M.A.
The Role of T Lymphocytes in the Development of Autoimmune Diseases: An Emphasis in the Mechanism of Action In Multiple Sclerosis abstract
Advisor: Kathryn Calame
Kristin J. Roman, M.A.
Drug Resistance in HIV-1 abstract
Advisor: Carol Lin
Sashiprabha Sathischandra, M.A.
The Regulation of Mammalian Rho GTPase Signaling abstract
Advisor: Scott Soderling
Aleksandr Serebrov, M.A.
Drug Delivery Systems Achievements and Opportunities abstract
Advisor: Larry Chasin
Jacob Sunshine Sherkow, M.A.
Allelospecific vs. Ethnospecific Cardiac Pharmacogenetics: Biochemical, Social, and Ethical Issues abstract
Advisor: Robert Pollack
Gregory A. Shostak, M.A.
Proteasome Inhibition in Anti-Cancer Therapy: The Case of Bortezomib and Multiple Myeloma abstract
Advisor: Thomas Franke
Robert Carlton Ward, M.A.
Targeting Costimulatory Pathways to Increase the Efficacy of Cancer Vaccines abstract
Advisor: Howard L. Kaufman
Hsan-au Wu, M.A.
Learn From Nature: Potent Herbal Medicine in Cancer Chemopreventions and Therapies abstract
Advisor: Linda S. Einbond
Pao-Shu Wu, M.A.
Development, Structure and Plasticity of Drosophila Neuromuscular Junction Synapse abstract
Advisor: Brian McCabe
Schizophrenia: Etiology, Neurobiology, and Treatments
Si-Wei Chen, M.A. 2006
Schizophrenia is a chronic and debilitating mental illness afflicting a large proportion of the population. Individuals suffered from this illness display devastating symptoms such as psychosis, negative symptoms, and cognitive dysfunction, all of which inevitably lead to long-term impairments in social and occupational functioning. While several genetic and environmental vulnerability factors have been implicated in thepathogenesis of schizophrenia, the actual causes and pathophysiology of this disorder remain largely unknown. Moreover, although treatments are available to alleviate some of the symptoms, their overall efficacy on improving functional outcome is still less than satisfactory. This review summarizes the current findings with regard to the etiology, neurobiology, and treatment options of schizophrenia; the challenges and future directions in this field will also be discussed. While recent advances provide new insights into understanding of the pathogenesis of schizophrenia and present opportunities for development of safer and more effective treatments, much about this disorder awaits to be elucidated before it is possible not only to cure but also to identify precise risk factors allowing preemptive prevention measures.
Bacterial and Human AlkB Proteins Repair DNA Alkylation Damage in Human Cells
Ming-Hui Cheng, M.A. 2006
The Escherichia coli AlkB protein is a 2-oxoglutarate- and Fe2+-dependent dioxygenase, catalyzing repair of nucleotide bases damaged on endocyclic ring nitrogens caused by SN2 alkylating agents like methyl methanesulfonate. Cell viability and proliferation assays are adapted to assess physiological effects of bacterial and human AlkB proteins on the protection of HeLa S3 Tet-Off cells to SN2 alkylating agents, but not to SN1 alkylating agents. Moreover, in vitro AlkB inhibition assays are applied to screen likely AlkB inhibitors, and test whether they are able to inhibit human AlkB homologues in vivo and thus attenuate cellular resistance to SN2 alkylating agents. Cell viability and proliferation assays used in the study are quite noisy, especially the MTT assay, probably because HeLa S3 Tet-Off cells are too resistant to SN2 alkylating agents. Besides, HeLa S3 Tet-Off cells are even more resistant numerically compared to cells that are usually used for these assays in the previous work. In a former study, HeLa S3 Mer- cells which do not express the human O6-methylguanine DNA methyltransferase were used, and are much more sensitive to SN2 alkylating agents. Thus, human cells with a higher sensitivity towards SN2 alkylating agents are likely to be needed to see effects.
The Applications of Pharmacogenomics in Clinical Drug Development
Yi-Shan Chou, M.A. 2006
Pharmacogenomics is concerned with the genetic variances that contribute to the variable effects of drugs in different individuals. Decades of research has provided substantial knowledge about the genetic mechanisms in connection with the therapeutic effects and toxicity of many medications. Efficacy pharmacogenomics and safety pharmacogenomics are frequently reviewed at various drug development stages. Most of the studies have used samples obtained from clinical trials in a retrospective fashion. Factors that influence the integration of pharmacogenomic approaches into the drug development process include the number of samples required to be studied, the logic of clinical application, the ease of use of an analysis test, and the current medical needs. The regulatory agency has also become involved in the advancement of pharmacogenomics and envisioned its use for the development of new diagnostic procedures and therapeutic agents that could achieve higher efficacy and better safety profile.
The Pharmacological Treatment of Tourette's Syndrome
Akiva Felt, M.A. 2006
Tourette’s Syndrome (TS) is a neurological disorder that exhibits a host of symptoms, the most prevalent being repetitive twitches known as tics. Different avenues of scientific research conducted over the past 25 years have all led to a consensus that the pathology of TS has complicated genetic roots and involves several neurotransmitter systems. The complex biological nature of TS is further reflected in the difficulties surrounding its treatment with pharmacological drugs. Numerous drugs developed to target different neurotransmitter systems have been found through off-label use to be successful at reducing tics. However, the efficacy of these drugs varies significantly among patients, and side effects commonly arise which require patients to discontinue treatment. Patients must often spend lengthy trial and error periods with several drugs until a suitable one is found. The objective of this paper is to refocus the landscape of TS drugs in order to simplify the treatment process. After discussing the clinical features and etiological origins of TS, the drugs currently available for treating TS are presented. Using methods outlined in this paper, data from the clinical trials of these drugs is utilized to create guidelines for facilitating the pharmacological treatment of TS. Finally, a financial model for projecting the revenues of different drugs being developed to treat the same disorder is presented. This model can be used when limited amounts of clinical data are available (e.g., phase II) and utilizes the same strategies employed for creating the TS treatment guidelines
RNA Interference; Very Promising, But Will it Deliver?
Aileen Fitzmaurice, M.A. 2006
RNA Interference is an endogenous form of gene regulation which was identified a mere 8 years ago. This system has been harnessed to exogenously silence gene expression in vitro and in vivo and has thus revolutionized the way in which gene function is studied. Once this exogenous form of gene silencing was found to be effective in mammalian cells the potential of RNA Interference in the development of therapies for a range of human diseases sky rocketed. In the biotechnology industry we have witnessed over and over again great enthusiasm for new technologies that frequently lead to a dead end. Will RNA Interference succeed in developing a plethora of effective human therapies or be a total washout? This paper reviews how RNA Interference was stumbled upon, the mechanism of silencing genes at the RNA level, the importance of RNA Interference in vivo, then attempts to analyze the progress of RNA Interference in pre-clinical and clinical studies in order to determine whether the scientific community is overly optimistic about RNA Interference.
Biology of GIST: Molecular Mechanisms and Target Therapy
Tianhua Guo, M.A. 2006
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal (GI) tract. It is considered to originate from interstitial cells of Cajal (ICCs), an intestinal pacemaker. KIT and PDGFRA activating mutations were found in more than 90% of GISTs. KIT mutations account for most of the cases, whereas only 2-5% of the GISTs carry PDGFRA mutations. About 10% of GISTs show oncogenic mutations in the extracellular domain of KIT (exon 9), while rare cases show mutations in the first or second kinase domain, exon 13 and 17, respectively. The remaining 5-10% of GISTs, so called wild-type GISTs, lack detectable KIT or PDGFRA mutations. GISTs have a homogeneous gene expression profile that distinguishes them as a group from other soft tissue sarcomas. Nevertheless, there is considerable transcriptional heterogeneity when comparing different pathologic or molecular subsets of GISTs. Gene expression in GIST depends on tumor location and KIT/PDGFRA genotype. In correlation with the distinct gene expression profile, the responsiveness of GISTs to the treatment with the front-line drug, imatinib, a tyrosine kinase inhibitor, varies depending on the exonic locations of KIT/PDGFRA mutation. During the chronic course of imatinib treatment, about half of patients will develop secondary drug resistance after an initial response. Only 5-10% of patients are completely insensitive to imatinib, so-called primary resistance. Given these facts, several second-generation tyrosine kinase inhibitors are in the process of being tested in preclinical studies or clinical trials, showing promising efficacy in imatinib resistant GISTs. The molecular mechanisms of GISTs oncogenesis and targeted therapy are being emphasized in detail in this review
Will Advexin Lead the US Towards a Brighter Future in Gene Therapy?
Asya Haney M.A. 2006
Advexin (INGN 201, Ad5CMV-p53) is a novel therapeutic approach to target tumor cells containing mutated p53 gene. So far the results of Advexin studies show that it is a well-tolerated and effective treatment for squamous cell carcinoma of the esophagus as monotherapy and in combination with radiation or chemotherapy agents. Studies demonstrated that intratumoral administration of Advexin is a feasible and well-tolerated method for therapeutic p53 gene transfer in patients with esophageal cancer. Advexin p53 therapy was shown to have a broad applicability in a wide range of tumor types. It has demonstrated clinical benefits in many tumor types in phase I and II clinical trials. Advexin targets p53 which is one of the most fundamental and common molecular defect associated with tumor formation and poor prognosis. It was approved by the FDA for a fast track program for an unmet medical need. Advexin was also designated as an orphan drug use for recurrent cancer of head and neck. A request for accelerated approval for Advexin is now pending at the U.S. Food and Drug Administration.
Slow versus Fast Muscle Derived Stem Cells for Muscle Regeneration in mdx Mutant Mice
Danielle H. Ho, M.A. 2006
Muscle regeneration following injury depends on muscle- specific stem cells known as satellite cells. Recently, it has become evident that in addition to satellite cells, muscle fiber also contains stem cells that can differentiate into both muscle and hematopoietic cell lines. Despite the significant potential clinical uses of this observation, little is known about the factors that regulate this process. This ambitious grant proposal aims to identify the range of phenotypic plasticity which resides in muscle derived stem cells (MDSC). More specifically, this grant proposes to decipher the potentiality of slow twitch MDSC, fast twitch MDSC, and MDSC of various ages. Understanding the breadth of phenotypic expression patterns will enhance the rehabilitating therapies for muscular dystrophic disorders.
Autoimmunity and Mechanisms of Immunosuppression
Kathy E. Karasiewicz, M.A. 2006
The immune system is a versatile system that houses the artillery to protect the human body from invading pathogens and cancer. The innate and adaptive immune systems work cooperatively in protecting one from such “non-self” invading pathogens and cancer, while distinguishing the body’s own cells as “self”. In some instances, this ability to discriminate between “self” and “non-self” is distorted and the immune system will begin to mount an inflammatory response to self, eventually leading to autoimmune disease. Currently, immunosuppressant drugs serve as therapies for autoimmune disease, but are limited by their non-specific, systemic immunosuppressive effect. In this review, we explore two endogenous molecules, HLA-G and Fas ligand, and two endogenous cell types, Regulatory T cells and Mesenchymal Stem Cells, as possible alternative therapeutic strategies for autoimmune disease. Herein, we investigate their mechanisms of action in inhibiting immune responses, as well as their current uses, potentials, and limitations. We conclude our discussion by comparing the use of HLA-G, Fas ligand, Regulatory T cells and Mesenchymal Stem Cells as therapies for autoimmune diseases to conventional immunosuppressant drugs.
The Prospect of DNA Sequencing Technology
Yuan-Chieh Ku, M.A. 2006
The Sanger sequencing method has dominated the field of molecular genetics for the last 3 decades. Automation of the Sanger method made possiblethe Human Genome Project. After 13 years and an outlay of more than 3 billion dollars, the sequence of the human genome was completed in 2003. This achievement has led to seismic changes in many different fields, having major repercussions for scientific and social issues. Scientists and researchers have begun to imagine the possibilities of the “personal genome” or “$1000 genome”. The Human Genome Project is clearly just the beginning. Many questions are unresolved in the post-genomic era. The demand for more efficient sequencing approaches has become more urgent than ever. Further improvements of the Sanger method are limited by the physical features of capillaries. In an effort to reduce costs, extend read lengths and increase throughput, many different groups have dedicated their efforts to developing novel sequencing systems. Another genetic revolution which should bear fruit in the near future is now underway.
Prion Diseases: Fatal Diseases to Be Tackled in the Biological Research, Public Health, and Legal Arenas
Jennifer J. Lee, M.A. 2006
The disease-associated prion proteins, as the causative agents responsible for transmissible spongiform encephalopathies, have been the subject of much controversy and scientific research. Many questions remain unanswered regarding prions and the prion disease mechanism. This article reviews the extent of current knowledge on prion diseases and recommends that (i) continued research efforts be made, (ii) individuals at every level of the beef distribution chain take personal, professional, and ethical responsibility to ensure that animal proteins do not get fed to cattle and that BSE-infected cattle do not enter the food chain leading to human consumption, and (iii) the federal government amend the current regulation to ban animal proteins from the non-ruminant feed also.
Middle Temporal Area’s Role in Visual Motion Processing: Motion Coherence
Ling Yue Lee, M.A. 2006
The middle temporal area (MT) of the visual cortex plays an important role in the primate visual motion processing. It receives the visual signal from V1, which is the striate cortex, and inherits most of its properties from V1. However, different from V1, MT neurons are directional selective and can recognize global motion of complex patterns. These neurons positively correlate with motion coherence and have stronger activities when the motion stimuli move more orderly. Also, the sensitivity of a single MT neuron is approximately the same as the psychophysical performance of the subject itself. These MT neurons are essential for visual motion processing and many developmental disorders have deficit in them. MT is not fully matured in human infants yet and they can not perform directional discrimination and movement- based perceptual skills like the adult. Instead, they only have a reflex response to motion coherence. MT neurons are necessary for visual motion perception and to recognize global motion from a group of visual stimuli that move randomly.
Human Papillomavirus, Transformation and Vaccination
Gregory Loiseau, M.A. 2006
500, 000 new cases of cervical cancer are diagnosed every year. Cervical cancer develops from the persistent anogenital infection by an oncogenic type of mucosatropic Human Papillomavirus (HPV). HPV16 and 18 are the most common types found in cervical carcinomas. With other high-risk types, they express viral oncogenes, namely E5, E6 and E7 which disrupt the cell-cycle regulation and prevent apoptosis and antigen presentation. When cellular and humoral responses fail to clear the infection, the lesions can then acquire the mutated phenotype and evolve into carcinoma. Cervical cancer differs from most cancers in that it offers exogenous targets for potential therapy. The portion of the HPV genome that encodes E6 and E7 is often integrated in cancer. In fact to maintain the transformed phenotype, the continuous expression of E6 and E7 is required. Today, 70% of cervical cancers can be avoided thanks to the recent introduction of a quadrivalent prophylactic vaccine to the market. There is still however, a strong incentive to develop a therapeutic vaccine that would help relieve the current cancer burden.
The War on Cancer with Emphasis on New Developments in p53, EGFR, and VEGF
Jamie L. Maddux, M.A. 2006
Cancer is the second leading cause of death in the United States and will become the first leading cause of death in the near future. The “War on Cancer” is in full force. However, the fight against cancer is a challenging battle. Meanwhile, there have been many changes in the way cancer research is conducted over the past three decades. For one, breakthroughs in basic research have increased our understanding of tumor development and progression. Some key areas of research are now more focused on some hallmarks of cancer, including self-sufficiency in growth signaling, the ability to evade apoptosis, and the ability to induce pro-angiogenic activity. Scientists have honed in on key players of tumorgenesis, such as p53 homologues and regulators, epithelial growth factor (EGF), and vascular endothelial growth factor (VEGF), all of which have been implicated in a variety of cancers. In addition, the ability to evade immune response has also been identified as an important hallmark of cancer. Such breakthroughs in these areas of research have resulted in the development of several successful cancer therapeutic agents currently being used to treat a variety of cancer types. Furthermore, successful research discoveries and drug development can be attributed to advancements in technologies such as flow cytometry, RNAi and the use of monoclonal antibodies. Although advancements in cancer research have not progressed as quickly as the scientific community had hoped, extraordinary breakthroughs in cancer research and drug development are now improving the survival rate and quality of life of millions of cancer patients. This review focuses on pivotal areas of research that have resulted in the development of some novel cancer therapeutic agents.
Interstrand Crosslinks: Characterization, Repair, and Clinical Significance
Daniel J. Moskovic, M.A. 2006
DNA damage presents challenges to both a functional and a replicating cell. Recent research has characterized the removal of intrastrand DNA damage by Nucleotide Excision Repair (NER), and the repair of double strand breaks (DSBs) via the Double Strand Break Repair (DSBR) pathway. The formation of interstrand crosslinks (ICLs) within the DNA duplex by compounds such as psoralens and mitomycin C, poses a formidable challenge to the cell. Various proposed repair pathways utilize components of NER, DSBR, and translesion repair mechanisms. The inherent complexity associated with generation of DSBs within the cell, or the ability of a cell to mobilize repair mechanisms in various stages of the cell cycle, is essential for survival of the cell. Interestingly, characterization of specific ICL repair pathways may be dependant on the molecular structure of the DNA adduct. In general, NER facilitates the generation of a DSB intermediate that can repair the damage via homologous recombination. Alternatively, the cell possesses a means of bypassing the DNA damage using translesion polymerases that impose a high rate of mutation at the site of the lesion, but are capable of reconstitution of the DNA duplex to some extent. ICL inducing agents have been employed successfully as tumor therapy, given their cellular toxicity. In addition, Fanconi’s Anemia presents a hypersensitivity to ICL inducing agents, exposure to which accelerates the development of cancer in these patients.
Overview of Acne Vulgaris and Current Treatment Procedures
Sanaa Musvee, M.A. 2006
Acne vulgaris, commonly observed in adolescents, is a complex disease with many contributing factors. The acne bacteria propionibacterium acnes and an inflammatory cascade it elicits, along with hormones such as androgens and abnormal keratinization of skin cells, are thought to be some of the factors contributing to the disease. Heredity and other external factors such as diet and lifestyle may also play a role. Conventional treatments such as the use of retinoids, oral contraceptives, antibiotics, and antimicrobial agents help alleviate acne vulgaris to an extent. However, the use of these treatments is not free from side-effects. Natural substances such as tea tree oil also exhibit effects similar to the conventional treatments. However, most of the treatments do not specifically address the underlying causes of the disease. Furthermore, one of the most unfortunate consequence of acne vulgaris is not the disease itself, but the disfiguring scars it leaves behind if left untreated for too long. Therefore, better treatment options for acne vulgaris must be developed. Using existing information and carrying out further studies involving acne vulgaris can help achieve this goal. Future drugs targeting specific pathways or genes may provide beneficial therapies against acne vulgaris.
Mahwish Natalia, M.A.2006
Cancer has always been viewed as a disease of abnormally proliferated cells resulting from mutations accumulating over the years. In this model of cancer disease progression, the identity of the transformed cell is not specified nor can one fully explain the behavior of cancer cells. Hence, among the scientific community, an alternative model has recently gained preference over this model. Cancer is now being looked at as a disease of abnormally proliferated somatic stem cells, where mutations have disrupted their self-renewal process. Research of the past decade has successfully illustrated the relationship between normal somatic stem cells and cancer stem cells. The existing similarities between normal stem cells and cancer stem cells range from cell surface markers, to the hierarchal arrangement of both types of cells as well as the mechanisms controlling their self-renewal. In vivo studies have established cancer stem cells as the root of the problem in only three of the many cancers: Acute Myeloid Leukemia, Breast and the cancers of the Brain such as Medulloblastomas, and Glioblastomas. Further studies will be needed to prove their existence in other cancers. Cancer stem cell model has not only come close to identifying the tumor initiating cell, but has given the medical community hope of finding a cure by eliminating the cells that sustain the tumor growth and are responsible for its recurrence.
RNAi – Mode of Action and Therapeutic Implications
P. Peter Nguyen, M.A. 2006
RNA interfering (RNAi) phenomenon was discovered in 1998 when Fire and Mello introduced double-stranded RNA (dsRNA) in to the nematode worm Caenorhabditis elegans and found that it not only has sequence specific and potent gene silencing activities but it also has potential catalytic ability. Prior to this breakthrough discovery, antisense mechanisms with single stranded RNA are one of the few methods used to study genes functions. As the mechanism for RNAi continues to be studied, it has become the tool of choice to study gene functions because of its ability to easily and efficiently ‘knock-down’ target genes. The similar RNAi mechanism shared in plants, invertebrate, and vertebrates has opened up the question of the existence of a biological function for RNAi. Several theories have been proposed that RNAi is a natural defense mechanism against viral and foreign DNA. The main mode of action of the RNAi induced gene expression inhibition is through post-transcriptional gene silencing (PTGS.) In PTGS pathway, dsRNA is cleaved by a dimerized, anti-parallel Dicer molecule to produce small interfering RNAs or siRNAs. Small interfering RNA then binds to a RNA-induced silencing complex and activates the unwinding of the siRNAs. The antisense RNA strand that binds to the RISC (RNA-induced silencing complex) complex forms Watson-Crick pairing and cleaves the mRNA at the center region of the siRNA-mRNA duplex. For the past few years, biotech startups such as Sirna Therapeutics, Alnylam, and Acuity Pharmaceuticals have been developing therapeutic intervention based on this new technology to target chronic and debilitating diseases such as the wet form of age related macular degeneration (AMD) and Parkinson’s disease. Although these companies have made progress in achieving serum stability, cellular stability, and circulation time in a mouse model, achieving similar success in human is not certain. Although definitive toxicity data in patients are not yet known, there have been several recent publications that have shown RNAi to have non-specific effects. From Sirna’s preclinical programs, there were no serious side effects observed; however, human physiological conditions are vastly different from mice. The preliminary success of siRNAs for wet-AMD will be known in the next few months as Sirna Therapeutics and Acuity Pharmaceuticals will finish up and analyze their Phase I and Phase II trial, respectively. In the meantime, both companies and a host of others that want to get into the RNAi field continue to work on the method of delivery to achieve therapeutic levels with efficacy and safety.
The Role of T Lymphocytes in the Development of Autoimmune Diseases: An Emphasis in the Mechanism of Action In Multiple Sclerosis
Rocío Kennia Pérez, M.A. 2006
The mechanisms of autoimmune diseases have baffled scientists and medical professionals for decades. The therapeutic approaches are often limiting, unsuccessful and costly. Multiple Sclerosis is an autoimmune disease affecting over 2.5 million people world-wide, with healthcare-related costs exceeding $10 billion annually. Understanding the mechanism of the disease is the first step in developing prospective alternatives in treating the disease. It is believed that Multiple Sclerosis is a T cell mediated disease that gains access to the Central Nervous System by crossing the Blood-Brain Barrier. Further T cell activation leads to complex interactions between Antigen Presenting Cells, cytokines and other proteins that eventually target the Oligodendrocytes, the myelin-producing cells. Finding a cure for Multiple Sclerosis may be far ahead, but current research is shaping future breakthroughs.
Kristin J. Roman, M.A. 2006
Human immunodeficiency virus-1 is a rapidly mutating virus that utilizes host replication machinery to produce large amounts of the mutated virus. The high replication rate enables the virus to readily mutate, avoiding the exerted therapeutic pressures. Nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, protease inhibitors are therapeutic options and are often administered in multi-drug regimens. Resistance to each of the compounds currently available has been documented. Viral mutation and resistance that develop add to the complexity in treating patients. As researchers gain a greater understanding of the existing mutations and the mechanism to produce resistance, superior therapeutic agents can be developed.
The Regulation of Mammalian Rho GTPase Signaling
Sashiprabha Sathischandra, M.A. 2006
The Rho GTPases belong to the Ras super family of small, monomeric GTPases. They act as molecular switches by existing in either the inactive GDP bound state or the active GTP bound state. Three kinds of regulatory proteins regulate the activity of Rho GTPases. Guanidine nucleotide exchange factors (GEFs) are positive regulators of Rho GTPases. They participate in catalyzing the exchange of GDP for GTP to activate Rho GTPases. GTPase activating proteins (GAPs) and guanidine nucleotide dissociation inhibitors (GDIs) are negative regulators of the Rho GTPases. GAPs accelerate the intrinsic GTP hydrolysis of Rho GTPases and GDIs bind to the GDP bound Rho GTPases to inactivate them. In their active form, Rho GTPases interact with a plethora of effectors to initiate signaling cascades and play a role in regulating the actin cytoskeleton, microtubule dynamics, cell cycle progression, gene transcription and enzymatic activities. Mutations or aberrant expression of regulatory proteins and effectors of the Rho GTPases are linked with several diseases such as mental retardation, epilepsy, cancer, immunodeficiency and hematological diseases. These diseases indicate the importance of proper signaling by Rho GTPases in sustaining several biological functions. The regulatory proteins themselves are tightly regulated through various mechanisms to maintain accurate and efficient Rho GTPase signaling. The Rho GTPases and the proteins that modulate their activity are being studied to understand the mechanisms underlying the regulation of them and the diseases associated with the aberrant signaling of Rho GTPases.
Drug Delivery Systems Achievements and Opportunities
Aleksandr Serebrov, M.A. 2006
Although field of drug delivery systems is still emerging field; it has already become one of very important aspects in pharmaceutical and biotechnology industries. The significance of such development is multi-dimentional because of its relevance to developing formulations as well as to drugs in current use. Modernization of drug delivery systems is prevalent drive in bringing today’s drug market to levels of higher efficiency. In addition, patient compliance regulations will be positively altered alongside economic uplift of the industry. In my thesis, I would like to further explore considerable advances in the field of drug delivery systems; and its farfetching affects on biotech and pharmaceutical industries as a whole
Allelospecific vs. Ethnospecific Cardiac Pharmacogenetics: Biochemical, Social, and Ethical Issues
Jacob Sunshine Sherkow, M.A. 2006
Historically, the practice of medicine has sought to treat disease using compounds and extracts that have pharmacological properties. Heart disease currently affects millions of individuals in the United States alone, and consequently, many sufferers are prescribed pharmacological treatment. Due to the complex nature of heart disease, however, there is a great disparity in individual response rates to cardiac pharmaceuticals. The practice of medicine, therefore, has sought to elucidate the molecular mechanisms of heart disease and develop pharmaceuticals against these targets; this is known as “pharmacogenetics.” In an effort to simply define broad groupings of a population that are more likely to respond to a particular compound, developers of pharmacogenetics have relied on “race.” Such simplification fails to further understand heart disease or find heart disease susceptible alleles for 3 reasons: 1) there is enough allelic admixture among races to confound a study; 2) such studies often fail to take into account social differences among races, especially in the United States; 3) “race” itself is a poorly defined biological concept. These are particularly apt criticisms for 3 classes of pharmacogenetics: anti-inflammatories, renin-angiotensin inhibitors, and anti-hypertensives. DG-031, a model anti-inflammatory, has been shown to be particularly effective in individuals with a particular ALOX5AP allele. Originally thought only to be present in Scandinavians, some black patients have recently found success with the drug. ACE inhibitors, normally prescribed to hypertensive patients, are far less effective in black patients. Rather than a racially specific etiology, however, recent evidence suggests that equivalent effectiveness can be obtained by a simple increase in dosage. BiDil, an anti-hypertensive of unknown mechanism, is prescribed specifically for black patients. In turn, its success may lie not in a biological racial disparity but in differing stress levels between black and white patients due to social factors. The proper creation of cardiac pharmacogenetics rests on their development based on allelic, not racial differences.
Proteasome Inhibition in Anti-Cancer Therapy: The Case of Bortezomib and Multiple Myeloma
Gregory A. Shostak, M.A.
Carcinogenesis is one of the chief pathological results of dysregulation of the mechanisms governing cell growth, proliferation and differentiation, and also programmed cell death (or apoptosis, as it is commonly known). Unlike its “disorderly” counterpart necrosis, apoptosis is a physiological, rather than pathological, process, by which the tissue homeostasis in an organism is maintained. The central role of apoptosis in this vital process predicates its equally important role in the neoplastic pathology. One of the principal venues involved in programmed cell death is the proteasome (or ubiquitin-proteasome) system. The proteasome is a universally expressed (it is found in both cytoplasm and nucleus of all eukaryotic cells) and broadly active multiprotein catalytic complex, primarily implicated in degradation of key regulatory proteins, which is necessary for the maintenance of cellular homeostasis. It has been established for some time that proteasome inhibition results in cell cycle arrest, induction of apoptosis, and yields favorable results in anti-cancer therapy. Bortezomib (also known as PS-341 and VELCADE®, Millennium Pharmaceuticals, Inc. and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.), is the first proteasome inhibitor that has been approved for clinical use by the FDA (for patients that failed to respond to prior chemotherapy). Multiple myeloma is a neoplastic disease of hematopoetic tissue characterized by the pathological monoclonal expansion of plasma cells; despite the advances in anti-cancer therapy, it has remained resistant to conventional methods until the present moment. Bortezomib and other proteasome inhibitors have been shown to selectively affect malignant versus healthy cells; this selectivity is caused by activation of specific apoptotic mechanisms (to be reviewed in closer detail in the main body of this paper) in myeloma and melanoma cells, but not normal melanocytes, as a result of the drug’s action. In addition to inducing apoptosis, proteasome inhibition also results in inhibition of tumor angiogenesis and cell adhesion, as well as a decrease of growth factor production. All these elements contribute to the anti-tumor effect of proteasome inhibition, which validates their use as selective therapeutics for otherwise drug-resistant malignancies, such as multiple myeloma.
Targeting Costimulatory Pathways to Increase the Efficacy of Cancer Vaccines
Robert Carlton Ward, M.A. 2006
Cancer immunotherapies harness the potential of the body’s immune system to combat malignant tumors. The efficient induction and maintenance of a T-cell-mediated antitumor immune response is critical to realize this end. Achieving positive therapeutic responses has proven challenging, however, as tumor cells appear inherently effective at evading immune surveillance. The poor immunogenicity of these altered-self cells can be largely attributed to the suppressive nature of the local tumor microenvironment, owing in part to the decreased expression of costimulatory molecules. Costimulatory signals are key elements in the activation of T-cells, and the integration of these signals within T-cells largely determines the course of any cell-mediated immune response. For these reasons, costimulatory molecules are being incorporated as adjuvants to cancer vaccines. In this article, we will review the biological aspects, as well as the current and potential therapeutic applications of select members from the five different families of costimulatory molecules. The large majority of well-established T-cell costimulators belong either to the B7:CD28 or tumor necrosis factor (TNF):TNF receptor families of molecules. Whereas members of the former are critical in the initial and early stages of T-cell activation, those of the latter are most important in sustaining T-cell responses. The CD2-subset and integrin families, which are generally thought to function primarily as cellular adhesion molecules, have also proven capable of T-cell costimulation. Perhaps even more excitingly, members of the chemokine family are also implicated for their ability to costimulate T-cell activation, in addition to their well-known chemotactic properties. Importantly, while some redundancy exists, each molecule appears to provide a unique contribution toward determining the course of any give immune response. With a better understanding of these relative contributions and how to integrate the different signaling pathways, we can move toward rationally and responsibly targeting these pathways to fine-tune T-cell activation for safer and more efficacious antitumor immunity.
Learn From Nature: Potent Herbal Medicine in Cancer Chemopreventions and Therapies
Hsan-au Wu, M.A. 2006
From willow tree to pacific yew tree, aspirin to taxol, the products from Mother Nature amazed the pharmaceutical industry. Natural compounds have become more and more popular as daily life supplements and the subjects in cancer research. This paper aims to study the potential mechanisms of natural compounds in cancer chemoprevention. Recent studies showed that natural compounds act as chemoprevention agents not only by their scavenger hunting and neutralizing activity to reduce cancer incidence, but also by inducing several important prevention mechanisms in multiple steps of tumor formation, especially inducing cellular stress responses. In order to defend against unusual events or undesirable situations happening within the cell, cellular stress responses help to eliminate the stress by halting the cell cycle and inducing rescue systems. Five cellular stress responses are discussed in this study, 1) endoplasmic reticulum stress response, 2) oxidative stress response, 3) nutrient deprivation response, 4) inflammatory response, and 5) Heme deprivation response. Each stress induces a different eIF2α kinase which results in a different set of gene expression. Further, the study provides potential mechanisms involving cellular stress of three natural compounds, actein from black cohosh, (-)-epigallocatechin gallate from green tea, and rosmarinic acid from rosemary. Thus, the mechanisms involving cellular stress response alluded to in the study provide potent strategy and potential cancer targets of herbal medicine in cancer chemoprevention. Keywords: natural compounds, cancer chemoprevention, cellular stress respons
Development, Structure and Plasticity of Drosophila Neuromuscular Junction Synapse
Pao-Shu Wu, M.A. 2006
One of the most intriguing questions in neurobiology is how brain neural network wire together to form functional circuits and execute various functions such as sensory integration, motor activity, learning and memory. Synaptogenesis plays a crucial role in the formation of brain circuits. Synaptic connections have the plastic ability to change in response to different activities and experience throughout life. However, how genes and proteins orchestrate synapse development and growth is poorly understood. Drosophila neuromuscular junction (NMJ) synapse is an excellent model for addressing fundamental question about synapses. There are well-established genetics, cellular and molecular biology tools for manipulation of fly. The easy accessibility of NMJ synapse makes it suitable for imaging analysis and in vivo observation. The complete genome sequencing and bioinformatics facilitate the forward and reverse genetic screen. Finally, the development of Drosophila and vertebrates synapse is similar in cellular and molecular level and many molecules important for synaptogenesis are highly conserved in evolution. For the last two decades, most of our understandings in synaptogenesis such as axon guidance, target recognition and synapse plasticity result from fly nervous system. By elucidating the molecular and cellular pathways of synaptic formation and plasticity and the regulatory mechanisms affecting synaptic structure and growth, we may apply our understandings to novel strategy for the treatment of clinical neurological disorders such as amyotrophic lateral sclerosis (ALS), spinal muscle atrophy (SMA) and Parkinson’s disease in the future.